Chapter 14 Anticonvulsants
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This document summarizes several anticonvulsant drugs, including their mechanisms of action and metabolic pathways. It discusses how phenobarbital and primidone both metabolize to phenobarbital, which is responsible for primidone's pharmacological effects. Carbamazepine and oxcarbazepine are described as having similar mechanisms but oxcarbazepine does not induce liver enzymes and has fewer side effects. Gabapentin and pregabalin are said to compete for glutamate biosynthesis. The document provides details on several other anticonvulsants such as lamotrigine, topiramate, levetiracetam, tiagabine, ethosuximide, and
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Chapter 14 Anticonvulsants
- 1. Dy, Claire Anne R. Chapter 14 Anticonvulsants
- 3. Phenobarbital and Primidone (Mysoline) Primidone is metabolized by CPY2C9/19 to phenobarbital and phenylethylmalonamide (PEMA)
- 4. Phenobarbital and Primidone (Mysoline) The pharmacological action of primidone is mainly a result of the minor metabolite, phenobarbital. Primidone is much less potent/toxic than phenobarbital because most of the drug is rapidly degraded to the less potent metabolite, PEMA
- 6. Carbamazepine (Tegretol) CBZ, 5H dibenz[b,f]lazepine 5 carboxamide is an iminostilbene derivative of tricyclic depressants useful in generalized tonic-clonic and partial seizures The major metabolite pathway of CBZ is the formation of a stable metabolite, 10,11-CBZ expoide by cytochrome P450 isozyme CYP3A4 This reactive metabolite is further deacvtivated by the action of epoxide hydrolase to give inactive inactive 10,11-CBZ-diol that is excreted as the corresponding glucuronide
- 7. Oxcarbazepine (Trileptal) similar mechanism of action to CBZ except for its metabolic inactivation pathway Not a liver enzyme inducer With the presence of a carbonyl function at the C- 10 carbon, OXC is reduced to the corresponding CBZ-10-ol by the action of alcohol dehydrogenase that is excreted as its O- glucuronide or can be further oxidized to the 10,11-CBZ-diol as an inactive metabolite Have much fewer hepatic and idiosyncratic side effects associated with CBZ
- 9. Oxcarbazepine (Trileptal) OXC is a weak inducer of CYP3A4 and UDP- glucuroyl transferase and also inhibits CYP2C19 Drug-drug interactions with medications metabolized by these enzymes are to be expected
- 11. Gabapentin (Neurontin) Pregabalin (Lyrica) Are broad spectrum anticonvulsants with multiple mechanism of action They compete for the biosynthesis of L-glutamic acid because of their structural similarity to L- leucine
- 12. Gabapentin (Neurontin) Pregabalin (Lyrica) Have very little liability for causing metabolic based drug-drug interactions because they are not metabolized in humans 95% of drug is excreted unchanged through the kidney Gabapentin exhibits 65% bioavailability in low doses Pregabalin exhibits 98% bioavailability
- 13. Felbamate (Felbatol) Flurofelbamate Broad spectrum of action A carbamate ester of 2-phenyl-1, 3-propanediol Stable to esterases Provides good oral bioavailability Associated with severe side effects such as aplastic anemia, idiosyncratic reactions and hepatic failures
- 17. Lamotrigine (Lamictal) Effective against refractory partial seizures MOA – blockade of sodium channels that is both voltage and use dependent metabolized by glucuronidation Major inactive urinary metabolites isolated are 2- N-glucuronide (76%) and 5-N-glucuronide (10%) Coadministration with valproate increases the incidence of its idiosyncratic reactions
- 19. Topiramate (Topamax) derivative of naturally occurring sugar D-fructose a sulphamate substituted monosaccharide exhibits broad and potent antiepileptic drug actions at glutamate and GABA receptors
- 20. Topiramate (Topamax) similar structure to D-glucose oral bioavailability of 85% and 95% only 20% is eliminated by CYP2C19 and the remaining drug is excreted unchanged
- 21. Zonisamide (Zonegran, Excegran) A sulfonamide type anticonvulsant Recently approved for adjunctive therapy in the treatment of partial seizures Primarily metabolized by reductive ring cleavage of the 1,2-benzisoxazole ring to 2-sulfamoyl- acteyl-phenol
- 23. Levetiracetam (Keppra) Analog of the nootropic agent, piracetam does not have affinity to AMPA receptor thereby has no nootropic activity for treatment of Alzheimer’s disease have no affinity to GABA receptors, BZD receptors, various excitatory amino acid related receptors, or the voltage-gated ion channels
- 24. Anticonvulsants acts on a Selective Molecular Target
- 25. Anticonvulsants acts on a Selective Molecular Target Tiagabine Ethosuximide Methsuximide Vigabatrin Benzodiazepines
- 26. Tiagabine (Gabitril) Blocks GABA reuptake as a major mode of its anticonvulsant activity Used against partial seizures Nipecotic acis is a potent inhibitor of GABA reuptake into synaptosomal membranes, neurons, and glial cells 90% is metabolized by CYP3A4 isozymes Primary site of metabolic attack is the oxidation of the thiophen rings leading to 5-oxo-tiagabine
- 29. Ethosuximide (Zarontin) Methsuximide (Celontin) Ethosuximide is needed for treating patients with absence seizures Works by blocking the low threshold T-type calcium channels, thereby reducing the hyperexcitability of thalamic neurons that is specifically associated with absence seizure
- 31. Vigabatrin (Sabril) A 4-vinyl analog of GABA Produces pharmacological action by irreversibly blocking GABA catabolism catalyzed by GABA-T Treatment of partial seizures
- 34. Clonazepam (Klonopin) Useful in absence seizures and in myoclonic seizures Tolerance often developed quickly metabolized by hydroxylation at C-3 position followed by glucuronidation and nitro group reduction and acetylation
- 36. Diazepam (Valium, Diastat) Valium is given orally Diastat is given rectally As an adjunctive treatment of generalized tonic- clonic status epilepticus or with refractory epilepsy in combination with other AEDs